High rates of relapse to drug use after prolonged drug-free periods characterize the behavior of experienced heroin and cocaine users. The behavioral and neurochemical events that contribute to these high rates, however, are not well understood. Relapse can be induced in human subjects and laboratory animals by reexposure to the drug previously used, reexposure to environmental cues paired with drug self-administration, and by exposure to stress. We are using an animal model of relapse, a reinstatement model, to study brain systems and neurotransmitters involved in relapse induced by environmental stressors, conditioned drug cues and drug reexposure in heroin- and cocaine-experienced rats after prolonged drug-free periods. During the last year, we have studied the relationship between the duration of the drug-free period and the propensity to relapse. The main finding of this line of research is that relapse to heroin and cocaine seeking is time-dependent and is not correlated with the severity of drug withdrawal. We also have identified several brain systems involved in intermittent footshock stress-induced relapse to heroin seeking, including the lateral tegmental noradrenergic neurons and the medial septum. In other studies, we found a role for D1-like dopamine receptors in relapse to drug seeking induced by contextual drug cues. In another set of studies, we found that acute, 1-day food deprivation provokes relapse to heroin seeking, an effect attenuated by central injections of leptin, a hormone involved in energy balance and food intake. Finally, we have modified our reinstatement model to study relapse to cocaine seeking in mice. To this end, we found that conditioned cocaine cues reliably reinstate cocaine seeking. We currently study the effect of stressors and cocaine reexposure for their effects on relapse in mice.